Abstract
BackgroundHuman endogenous retroviruses (HERVs) belong to the LTR-retrotransposon family, where the complete HERV sequence contains two long terminal repeats (LTRs) located at each end. Intact LTRs possess highly conserved transcriptional promoter and enhancer sequences, so analyses of HERV insertional polymorphisms are expected to provide greater insights into human genomic variation compared with the conventional analysis of single nucleotide variations. High-throughput sequencing technology is developing but genome-wide investigations of HERVs are methodically challenging, and thus a comprehensive understanding of HERV insertional polymorphisms and target site duplications (TSDs) remains elusive.ResultsWe identified five human-specific insertionally polymorphic sites in HERVK (HML-2), one of the HERV subgroups, by extracting HML-2-deleted sequences from the genomic structural variation database, which we successfully characterized and then updated the existing catalogue of HML-2 insertional polymorphisms. The insertionally polymorphic states were confirmed in a small Japanese population by genomic PCR analysis for four of the five sites identified. Sequencing of the preintegration sites clearly showed that the HML-2 site located at 7p21.2 had 250-base pair (bp) TSDs, which is one of the longest TSDs in HML-2. In addition to these five sites, another insertionally polymorphic site for a non-human-specific HML-2 site was also identified at 6p25.2, which was flanked by 111-bp TSDs and the corresponding ERV locus was also annotated in the genome of non-human primates.ConclusionsOur analysis demonstrated the existence of HERV insertions flanked by unconventionally long TSDs, including those with lengths as high as 250 bp. This suggests that the length range of retroviral TSDs is larger than considered previously, which might help to understand how retroviral integration occurs in the host genome.
Highlights
Human endogenous retroviruses (HERVs) belong to the Long terminal repeat (LTR)-retrotransposon family, where the complete HERV sequence contains two long terminal repeats (LTRs) located at each end
The two elements located in 19p12b and Xq21.33, where the former is known as K113, are intact proviruses in terms of all viral proteins and most Human mouse mammary tumor virus like-2 (HML-2) loci are present as a solo LTR (sLTR) [3, 4]
To extract putative insertionally polymorphic sites from the HML2_LTRs, Database of Genomic Variants (DGV) data were first analyzed by a custom-made Perl script, which is available via GitHub, with the following filters: (i) DGV variant subtype “loss” or “deletion”; (ii) deletional regions covering the HML-2_sLTR sequence; and (iii) length of the deletional region shorter than 1500 nucleotides
Summary
Human endogenous retroviruses (HERVs) belong to the LTR-retrotransposon family, where the complete HERV sequence contains two long terminal repeats (LTRs) located at each end. Intact LTRs possess highly conserved transcriptional promoter and enhancer sequences, so analyses of HERV insertional polymorphisms are expected to provide greater insights into human genomic variation compared with the conventional analysis of single nucleotide variations. High-throughput sequencing technology is developing but genome-wide investigations of HERVs are methodically challenging, and a comprehensive understanding of HERV insertional polymorphisms and target site duplications (TSDs) remains elusive. Insertions and deletions (indels) of long sequences are technically difficult to detect compared with single nucleotide variations and a comprehensive understanding of indels remains elusive. An overall understanding of insertional polymorphisms in HERVs is not available at present due to the large sizes of the sequences (full length ~ 10 kbp) and the large number of copies (>200,000 loci), collectively accounting for about
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